This application claims priority of European patent application 122 751.5 filed Dec. 1, 1998 and European patent application 107 553.2 filed Apr. 15, 1999. The entire disclosure of the above patent applications is incorporated by reference herein.
The present invention relates generally to drug administration devices, and in particular to a liquid droplet spray device for atomizing a liquid substance such as a drug, a fragrance or other aerosolised or atomized liquids. Such a device may be used for administrating a drug to a patient by means of his or her respiratory system. Such an administration device, in its simplest form, is commonly called an inhaler. It may be used, e.g., for the controlled administration of drugs or for a variety of therapies using aerosolised drug administration including anesthetics. The inhaler delivers the drug, which is in the form of a liquid substance, as a dispersion of atomized droplets. More specifically, the present invention concerns an optimized liquid droplet spray device which efficiently creates and which fully expels a liquid droplet spray.
Various devices are known for atomizing a liquid. Document EP 0 516 565 describes am ultrasonic wave nebuliser which atomizes water. This apparatus is used as a room humidifier. Vibration is transmitted through the water to the water surface from which the spray is produced. A perforate membrane is provided to retain the water in absence of oscillation.
Typically, inhaler devices use the same principle to atomize the liquid into droplets, see for example the document WO 95/15822. However, such devices are particularly ineffective in vaporizing suspensions as explained in the Research Article  less than  less than Comparison of a respiratory suspension aerosolised by an air-jet and an ultrasonic nebuliser greater than  greater than  by Susan L. Tiano and Richard N. Dalby in Pharmaceutical Development and Technology, |(3), 261-268 (1996).
Furthermore, the droplet size which depends on the size of the outlet orifices of the perforate membrane, further also depends on the shape of the orifice and on the vibration frequency. In order to obtain a small droplet, a very high frequency should be used, typically over 1 MHz for droplets of about 10 xcexcm in diameter. This leads to an increased power consumption due to the high frequency so that such a device is not suitable for a small battery operated device.
With a large variation of droplet size, it is almost impossible to determine the expelled quantity and thus the actually-administered dosage.
Further, the orifices can not be made too small, not only because of fabrication reasons, but also in order to avoid clogging of the outlet orifices by the substance. In fact, it is known that the aqueous solubility of the substance solution depends on the composition of the drugs used and on its temperature. It is also known that such orifices might be clogged by very small amounts of drug left in the liquid spray device after atomization.
To ensure that a certain amount of substance is indeed released, it has been proposed to monitor the amount of liquid released when the inhaler is used. The document WO 92/11050 describes such an inhaler having means for cyclically pressurizing the liquid such that the liquid is periodically expelled and also having control means for deactivating the droplet generator after a predetermined time, e.g., by using a timer, or, after a predetermined volume of liquid has been expelled. However, this document is completely silent about droplet size control, aqueous solution or suspension characteristics as well as about any deposition target determination and control of the liquid.
Another prior art device is known from the document U.S. Pat. No. 5,497,763. This device has a breath actuated release of aerosolised drug and has a porous membrane located above a dosage unit container. The pores are preferably cone-shaped to reduce the force needed to move the drug substance there through when collapsing the container. However, such a membrane is difficult to manufacture, as the reproducibility of the pores is poor. Also, the difference in length and diameter of the pore channel results in a considerable difference of pressure drop across this channel. This varying pressure drop will thus also lead to a variation of the quantity and droplet size dispersion of the drug being expelled. Another problem is the alignment of the movable membrane with pores over each unit container resulting in another source of uncertainty over the expelled amount of drug.
The pre-cited documents are silent about avoiding layers or areas of liquid drug forming on the outside surface of the nozzle array by well-known capillary action and stiction. This is especially the case with devices where the same nozzle array is used several times, such as for example in the documents WO 92/11050 or WO 90/01997. Such layers lead to the forming of liquid meniscus in front of the nozzles which are broken up by the piezo-activated spraying action but lead to a larger droplet size dispersion than without such layers.
Although the cited document U.S. Pat. No. 5,497,763 partially overcomes this problem by separating dosage containers and the porous membrane through which the drug is aerosolised, this solution does not allow for the precision and repeatability of the cone-shaped pores used and the precise control of the drug delivery, requiring a pressure to be applied additionally to the piezoelectric vibrating means to force the liquid out. Also, the pre-cited documents do not mention that the piezoelectric vibrating means is not compensated for its non-linearities adding to uncontrolled factors affecting the delivery of targeted delivery.
The document U.S. Pat. No. 4,605,167 also describes a liquid droplet spray device for use in a fuel injector or an ink jet printer. The spray device comprises a housing provided with a liquid containing space and having a top substrate forming a membrane and provided with outlet nozzles therein. A piezoelectric actuator is attached to the membrane to vibrate the latter thereby causing the ejection of the liquid which is sucked out of the space by the vibrating membrane. Thus, when the membrane deflects inwardly towards the liquid, it compresses the latter and by expanding again, the created pressure in the liquid ensures the droplet ejection, i.e. the liquid is sucked towards the membrane and is expelled through the outlet nozzle. Another prior art document which basically functions according to the same principle is known from U.S. Pat. No. 5,828,394.
However, such spray devices suffer from the inability to fully empty the liquid in the space. Indeed, if the liquid is a suspension containing solid particles, these particles will not be sucked towards the membrane because they are too heavy. Thus, a precise dosing is not possible, because the retention cannot be determined. Furthermore, the pressure created in the liquid by the incoming membrane causes another problem related to the ejected droplet. Indeed, a droplet that is ejected through the outlet nozzle usually has a pear-shape, with the large body part tearing apart at the exit, and a smaller cut-off tail part thus being ejected slightly later. However, due to the pressure of the liquid, the tail part will regain the body part, and the total large droplet impacts simultaneously the target. It may be thus understood that an exact determination of the expelled amount of liquid and an exact control of the droplet size are impossible.
It is, therefore, an object of the present invention to provide an improved liquid droplet spray device for an inhaler suitable for respiratory therapies which overcomes, at least partially, the inconveniences of the prior art and which allows for an optimal flow of the atomized substance and which allows for a minimal retention of the substance in the spray device after expelling so that a precisely determined quantity may be expelled.
It is another object of the present invention to provide such a device which is simple, reliable to manufacture, small in size and low in cost.
Thus, the present invention concerns a liquid droplet spray device as disclosed and described herein.
Thanks to the specific shape and the positioning of the outlet means of the spray device according to the present invention an optimal throughput and flow together with a minimal retention of the atomized liquid in the spray device is obtained so that a precise dosage of expelled liquid may be determined.
Further, the inventive spray device may be re-used for a certain number of doses, because, due to the minimal retention, there is a minimal risk of increased drug concentration or drug contamination with remains of the previously used liquid.
Further, thanks to the inventive spray device, only a minimal amount of liquid is used, as the exact amount released can be predetermined with a high precision so that there is only a very small amount of waste and that the side effects can be limited too.